There are at least three different opioid receptors (μ, δ, and κ) that are present in both central and peripheral nervous systems of many species, including humans. Lord, J. A. H., et al., Nature, 1977, 267, 495. Activation of the δ-opioid receptors induces analgesia in various animal models. Moulin, et al., Pain, 1985, 23, 213. Some work suggests that the analgesics working at δ-opioid receptors do not have the attendant side effects associated with μ and κ opioid receptor activation. Galligan, et al., J. Pharm. Exp. Ther., 1985, 229, 641. The δ-opioid receptor has also been identified as having a role in circulatory systems. Ligands for the δ-receptor have also been shown to possess immunomodulatory activities. Dondio, et al., Exp. Opin. Ther. Patents, 1997, 10, 1075. Further, selective δ-opioid receptor agonists have been shown to promote organ and cell survival. Su, T-P, Journal of Biomedical Science, 2000, 9(3), 195-199. The δ-opioid receptor was recently recognized to trigger and mimic ischemic preconditioning (Schultz, et al, “Ischemic Preconditioning and Morphine-Induced Cardioprotection Involve the delta-Opioid Receptor in the Intact Rat Heart”, J. Mol. Cell. Cardiol., 29: 2187-2195, 1997; Schultz, et al., “Ischemic Preconditioning is Mediated by a Peripheral Opioid Receptor Mechanism in the Intact Rat Heart”, J. Mol. Cell. Cardiol., 29: 1355-1362, 1997). An opioid role in human preconditioning was further demonstrated by Xenopoulos, et al., “Morphine Mimics Ischemic Preconditioning in Human Myocardium during PTCA”, J. Am. Coll. Cardiol., 65: 65A 1998 with the application of intracoronary morphine as a mimic for preconditioning. Other reported developments include the use of δ-opioid receptor agonists to reduce myocardial infarct size (Watson, et al., J. Pharm. Exp. Ther. 316: 423-430 (2006)) and to reduce ischemic damage or provide cardioprotection for example, from myocardial infarction (WO 2004/060321 A2; WO 99/04795). Ligands for the δ-opioid receptor may therefore find potential use as analgesics, antihypertensive agents, immunomodulatory agents, and/or agents for the treatment of cardiac disorders.
Numerous selective δ-opioid ligands are peptidic in nature and thus are unsuitable for administration by systemic routes. Several non-peptidic δ-opioid receptor ligands have been developed. See, for example, E. J. Bilsky, et al., Journal of Pharmacology and Experimental Therapeutics, 1995, 273(1), 359-366; WO 93/15062, WO 95/04734, WO 95/31464, WO 96/22276, WO 97/10216, WO 01/46192, WO 02/094794, WO 02/094810, WO 02/094811, WO 02/094812, WO 02/48122, WO 03/029215, WO 03/033486, JP-4275288, EP-A-0,864,559, U.S. Pat. Nos. 5,354,863, 6,200,978, 6,436,959, and US 2003/0069241.
While there are a large number of non-peptidic δ-opioid receptor modulators, there is still an unfulfilled need for compounds with selective δ-opioid receptor activity that may be used in methods to provide beneficial pharmaceutical characteristics while minimizing undesirable side effects. The present invention is directed to these, as well as other important ends.